Reduced erythrocytic CHCHD2 mRNA is associated with brain pathology of Parkinson\u2019s disease

Xiaodan Liu,Yiran Hou,Eric Thorland,David Soltys,Eugene M Cilento,Genliang Liu,Ying Yang,Tessandra Stewart,Tao Feng,Jing Zhang,Zongran Liu,Min Shi,Qilong Wang

doi:10.1186/s40478-021-01133-6

Abstract

Peripheral biomarkers indicative of brain pathology are critically needed for early detection of Parkinson’s disease (PD). In this study, using NanoString and digital PCR technologies, we began by screening for alterations in genes associated with PD or atypical Parkinsonism in erythrocytes of PD patients, in which PD-related changes have been reported, and which contain ~ 99% of blood α-synuclein. Erythrocytic CHCHD2 mRNA was significantly reduced even at the early stages of the disease. A significant reduction in protein and/or mRNA expression of CHCHD2 was confirmed in PD brains collected at autopsy as well as in the brains of a PD animal model overexpressing α-synuclein, in addition to seeing a reduction of CHCHD2 in erythrocytes of the same animals. Overexpression of α-synuclein in cellular models of PD also resulted in reduced CHCHD2, via mechanisms likely involving altered subcellular localization of p300 histone acetyltransferase. Finally, the utility of reduced CHCHD2 mRNA as a biomarker for detecting PD, including early-stage PD, was validated in a larger cohort of 205 PD patients and 135 normal controls, with a receiver operating characteristic analysis demonstrating > 80% sensitivity and specificity.

Highlights

Diagnosis of Parkinson’s disease (PD), a common neurodegenerative disorder [28], is currently based on a combination of medical history, observation of cardinal motor indicators, and response to pharmaceutical therapies [42, 47]
Reduced mRNA and protein expression of CHCHD2 in erythrocytes of PD patients A NanoString multiplex gene expression method was used to screen for potential mRNA biomarkers for PD within erythrocytes
A panel of 21 genes associated with PD or atypical Parkinsonism chosen based on previous reports [6, 18, 20, 34, 43], was examined in a cohort consisting of 48 participants separated according to four diagnostic classifications: control, early-stage PD (Early PD), middle-stage PD (Mid PD), or late-stage PD (Late PD) patients according to Unified Parkinson’s Disease Rating Scale (UPDRS) score (Additional file 1: Table S1). mRNA expression frequency of each gene in erythrocytes of healthy control is shown in Additional file 1: Fig. S1, with SNCA, FBXO7, CHCHD2, PSEN1, LRRK2, VPS35, GATA1, MAPT, APOE, and PINK1 among the ten most highly expressed genes in erythrocytes

Summary

Introduction

Diagnosis of Parkinson’s disease (PD), a common neurodegenerative disorder [28], is currently based on a combination of medical history, observation of cardinal motor indicators, and response to pharmaceutical therapies [42, 47]. Much effort in the PD biomarker field has focused on the discovery of biomarkers using the cerebrospinal fluid (CSF), with α-synuclein and its variants receiving most attention [32, 41, 45]. Very few markers investigated far demonstrate clinically useful power in detecting PD or following PD progression, and none has been widely validated. Alongside the challenges associated with these protein markers, CSF collection (via lumbar puncture), often perceived as a high-risk and painful procedure, is impractical for routine screening purposes. Investigations on PD-related proteins in blood have received more consideration; they

Methods

Results

Conclusion